Recent evidence suggests that damage to the forebrain monoaminergic systems may be among the neurotransmitter systems contributing to responsivity to cholinomimetic therapy. Thus future pharmacological treatment strategies should be based upon the treatment of the multi-transmitter system deficits of AD. Animal model systems must therefore be developed which allow a) the evaluation of the cognitive consequences of multiple transmitter system deficits and b) determination of necessary pharmacological approaches for the alleviation of cognitive deficits in animals sustaining multi- transmitter system damage. The studies proposed in this application are designed to at least partially satisfy these requirements. In addition to continuing our work on the consequences of noradrenergic and cholinergic lesions on the efficacy of cholinomimetic drugs in reversing forebrain cholinergic lesion-induced memory deficits, we will evaluate some of the mnemonic consequences of forebrain serotonergic lesions, both alone and in combination with cholinergic lesions. We also intend to develop and evaluate pharmacological treatment strategies for the alleviation of memory deficits caused by combined cholinergic and serotonergic lesions.